Several homeoprotein transcription factors transfer between cells and regulate gene expression, protein translation, and chromatin organization in recipient cells. ENGRAILED‐1 is one such homeoprotein expressed in spinal V1 interneurons that synapse on α‐motoneurons. Neutralizing extracellular ENGRAILED‐1 by expressing a secreted single‐chain antibody blocks its capture by spinal motoneurons resulting in α‐motoneuron loss and limb weakness. A similar but stronger phenotype is observed in the Engrailed‐1 heterozygote mouse, confirming that ENGRAILED‐1 exerts a paracrine neurotrophic activity on spinal cord α‐motoneurons. Intrathecal injection of ENGRAILED‐1 leads to its specific internalization by spinal motoneurons and has long‐lasting protective effects against neurodegeneration and weakness. Midbrain dopaminergic neurons express Engrailed‐1 and, similarly to spinal cord α‐motoneurons, degenerate in the heterozygote. We identify genes expressed in spinal cord motoneurons whose expression changes in mouse Engrailed‐1 heterozygote midbrain neurons. Among these, p62/SQSTM1 shows increased expression during aging in spinal cord motoneurons in the Engrailed‐1 heterozygote and upon extracellular ENGRAILED‐1 neutralization. We conclude that ENGRAILED‐1 might regulate motoneuron aging and has non‐cell‐autonomous neurotrophic activity.
Conflict of Interest Statement: AP and KLM are on several patents for HP therapeutic use and co-founders of BrainEver. SEVA and ML are BrainEver post-doctorant and doctorant, respectively.Funding sources: MemoLife Labex PhD fellowship to SEVA, Association Nationale de la Recherche et de la Technologie (Cifre/ANRT n° 2017/0488) to ML, BrainEver, HomeoSign ERC -2013-AdG n°339379. ABSTRACTMotoneuron degeneration leads to skeletal muscle denervation and impaired motor functions, yet the signals involved remain poorly understood. We find that extracellular ENGRAILED-1, a homeoprotein expressed in spinal cord V1 interneurons that synapse on α-motoneurons, has non-cell autonomous activity. Mice heterozygote for Engrailed-1 develop muscle weakness, abnormal spinal reflex and partial neuromuscular junction denervation. A single intrathecal injection of ENGRAILED-1 restores innervation, limb strength, extensor reflex and prevents lumbar α-motoneuron death for several months. The autophagy gene p62, which was found to network with Engrailed-1 and amyotrophic lateral sclerosis genes, is misregulated in Engrailed-1 heterozygote mice α-motoneurons and is rescued following ENGRAILED-1 injection. These results identify ENGRAILED-1 as an α-motoneuron trophic factor with long-lasting protective activity.
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